H3.3S31ph acts as a molecular switch regulating the dynamic transition of nucleosomes from a stable to an activated state. Credit: Nucleic Acids Research (2025). DOI: 10.1093/nar/gkaf891
The serine 31 (Ser31) phosphorylation modification (H3.3S31ph) in the N-terminal tail of the histone variant H3.3 can transform H3.3 nucleosomes from a stable state to a dynamically activated configuration, providing new insights into the mechanisms of epigenetic regulation. However, the specific mechanisms by which H3.3 influences nucleosome stability and dynamics remain unclear.
In a new study published in Nucleic Acids Research on September 12, a research team led by Prof. Li Wei from the Institute of Biophysics of the Chinese Academy of Sciences, together with Prof. Chen Ping from the Capital Medical University, has, for the first time, uncovered how H3.3 and its Ser31 phosphorylation regulate nucleosome dynamics and transcriptional responses, highlighting the critical role of this mechanism in macrophage immune response pathways.
Using a combination of in vitro single-molecule experiments and genome-wide analyses, the researchers showed that although the incorporation of H3.3 does not significantly alter the mechanical stability of nucleosomes, it markedly enhances their ability to maintain integrity after disruption.
One key discovery was that H3.3 recruits the FACT complex (Facilitates Chromatin Transcription) more efficiently than canonical H3. FACT typically destabilizes nucleosomes, but when bound to H3.3-containing nucleosomes, it instead promotes a stable, maintenance-oriented state.
Precise characterization of the interaction between FACT and H3.3 nucleosomes using high-resolution single-molecule magnetic tweezers manipulation technology. Credit: Adapted from Nucleic Acids Research (2025). DOI: 10.1093/nar/gkaf891
The researchers also identified the phosphorylation of H3.3 at Ser31 as a critical molecular switch that reverses this stability. H3.3S31ph transforms the nucleosome from a stable state into a dynamic, active configuration that facilitates rapid transcriptional activation. This modification is specifically induced in macrophages upon stimulation, where it dynamically modulates FACT binding, nucleosome states, and the ensuing transcriptional response.
These findings provide novel mechanistic insights into how the interplay between a histone variant, its post-translational modification, and a histone chaperone complex can precisely regulate chromatin dynamics.
The study underscores the importance of H3.3S31ph as a pivotal regulator in enabling a rapid shift from transcriptional poising to activation in immune responses. It also suggests potential therapeutic implications in the treatment of diseases involving chromatin dysregulation, such as inflammatory disorders and cancer.
More information:
Jingzhe Ma et al, Phosphorylation of H3.3 at Serine 31 acts as a switch of nucleosome dynamics for transcription, Nucleic Acids Research (2025). DOI: 10.1093/nar/gkaf891
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How a histone ‘switch’ regulates chromatin dynamics (2025, September 27)
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